|J. Taylor Whaley, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
Skin, the largest organ in the body, serves numerous functions. The most obvious function of skin is serving as a barrier between the outside world and internal organs. Over the course of years of exposure, skin is exposed to numerous potential carcinogens, or cancer causing agents, most importantly the sun and its damaging ultraviolet rays.
Skin cancer is the most common type of cancer diagnosed each year. The incidence of skin cancers exceeds that of all other cancers, and it is estimated that nearly half of cancers diagnosed every year will be skin cancers. Moreover, it is estimated that nearly half of the general population that lives to age 65 will be diagnosed with a skin cancer in their lifetime. Over the past decade, the incidence of skin cancers has increased dramatically. In fact, the treatment of non-melanoma skin cancer has risen more than 70% since the early 1990’s. The median age at diagnosis for non-melanoma skin cancers is 68 years old, with men being 4 times more likely to be diagnosed with skin cancer. With this increasing rate of diagnosis, the average age of patients at diagnosis has continued to decline, with more young females being diagnosed every year. While more than 2 million skin cancers will be diagnosed in the United States in 2010, the mortality rate of non-melanoma skin cancers is around 0.3%, translating to only 2000 deaths per year. Most non-melanoma skin cancers will be diagnosed on areas of the body with excess exposure to the sun. Although these cancers can be locally progressive, they rarely metastasize or spread to other parts of the body. Because of early detection and the decreased metastatic potential, non-melanoma skin cancer is often effectively treated and cured with only local treatment.
What are the risk factors for developing skin cancer?
Risk factors for developing non-melanoma skin cancers are numerous, including fair complexion, occupational exposures to radium and arsenic, personal history of atypical moles, skin cancers, family history of skin cancers, smoking tobacco, immunosuppression from medications and HIV, chronic non-healing wounds and previous burns (Marjolin’s ulcers), genetic syndromes such as basal cell nevus syndrome and xeroderma pigmentosum, and HPV; however, the most common risk factor for development of skin cancer is exposure to ultraviolet radiation from the sun. The vast majority (90%) of skin cancers will occur in individuals with no risk factors other than excess sun exposure.
Ultraviolet radiation from both sun exposure and tanning salons damage the epidermis and the DNA in the cells found throughout the skin. This damage continues to occur with repeated exposure, eventually leading to mutations that accumulate to cause cancerous cells. It has been shown that severe sunburns are particularly damaging when they occur in children. Childhood sun exposure is the strongest correlate with the development of basal cell carcinomas, while sun damage in the decade preceding diagnosis is closely correlated with the development of squamous cell carcinomas.
Can skin cancers be prevented?
As with all cancers, the most effective treatment for skin cancers is prevention. The easiest approach to prevent skin cancers is the avoidance of exposure to ultraviolet rays from the sun and tanning salons. General recommendations from the American Cancer Society include avoiding prolonged, unprotected exposure to the sun between 10 A.M. and 4 P.M, as damaging UV exposure is greatest between these times. Further recommendations include wearing a long-sleeve shirt and hat when outside, wearing sunscreen and re-applying often, and limiting swimming activities to mornings and evenings when the sun is not at its hottest. Wearing sunscreen is crucial in prevention of skin cancers. Sunscreen with a sun protection factor (SPF) of 15 or greater should be worn everyday, even in the winter, on any uncovered surface, including our lips. Consistent use of sunscreen has even shown the ability to reduce further skin damage in people with a history of extensive sun exposure. These recommendations, while important for all people, are particularly vital for those with fair skin, light eyes, and red hair. Finally, and most importantly, teaching children the proper ways of avoiding sunburns is crucial for protecting their skin and promoting healthy skin habits in the future.
As we age, our years of sun exposure increase, and therefore the risk of skin cancer increases. Because of this increasing risk of cancer with age, it is crucial to examine our own skin regularly and to notice changes early. Be aware of the shapes and coloring of any freckles and moles you have. Skin cancer often develops from an existing lesion, causing its appearance to change. Examine your skin routinely in a mirror, including your back, face, lips, hands, forearms, and scalp. Furthermore, it is recommended that you follow up with your physician regularly. Early diagnosis is crucial in achieving the most appropriate treatment. Because skin cancers are related to exposures, people who have previously developed skin cancers are at much higher risk for future skin cancers, either in the primary (original) site or somewhere else on the body. Because of this, a complete skin exam should be performed by a healthcare provider at regularly scheduled visits.
What are the types of non-melanoma skin cancer?
Three primary types of skin cancers - basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma - account for most skin cancers. In fact, BCC accounts for 65% of all skin cancers, SCC accounts for 35%, and melanoma accounts for 1.5%.
In this discussion, I will focus on basal cell and squamous cell carcinomas. These cancers derive their name from the cells in which they originate. Both types of cells, basal and squamous, are located within the epidermis, or the outer layer of our skin. Pre-malignant lesions generally precede the development of non-melanoma skin cancers.
Actinic keratosis, which is a precancerous dry, scaly lesion, and carcinoma in situ (Bowen’s disease) are typically located in areas of significant sun damage and often possess the potential to become malignant basal cell or squamous cell carcinomas. These lesions initially develop into dysplasia, or atypical cells. Approximately 10% of actinic keratoses will develop into invasive cancer.
Bowen’s disease is an intraepithelial hyperplasia that is confined to the skin surface, also known as carcinoma-in-situ. As the dysplasia progresses into cancer, the tumor cells become invasive and destroy the basement membrane to invade deeper. Other less common types of skin cancers that I will not discuss here include Kaposi’s sarcoma and Merkel cell carcinoma.
Basal Cell Carcinoma (BCC)
BCC are commonly diagnosed in middle-aged and elderly individuals in skin that has been constantly exposed to the sun’s harmful rays for years. In patients with a history of skin cancer, nearly one-third of BCC arise in areas of actinic keratosis. Actinic keratosis is a precancerous lesion that develops in areas of repeated sun-damage.
BCC typically presents as a small pearly or crusty patch that fails to heal. Because they are painless and typically develop slowly, they are often present for months to years before they are brought to the attention of the healthcare provider. Often, BCC can be identified by blood vessels that are prominent within the bump. As the lesions grow, crusting and bleeding ulcers that will not heal are frequently the reason individuals present to their doctor. The lesions are most often identified on the face, with more than 70% of BCC diagnosed on the lips, cheeks, ears, nose, and scalp. Other regions of the body commonly diagnosed with BCC include the back of the neck, the shoulders, the forearms and hands, the back, and lower legs.
Although the lesions are slow-growing and rarely develop the ability to spread to lymphatics or other parts of the body, the lesions can progress locally, leading to destruction of nearby structures which can be disfiguring. Lesions are frequently neglected secondary to their slow growth. As the BCC grows, it may invade adjacent areas, including blood vessels, cartilage, and bone. Risk factors for recurrence after treatment of basal cell carcinomas include depth of invasion, pathologic sub-type, and perineural invasion.
Squamous Cell Carcinoma (SCC)
Like BCC, SCC is commonly diagnosed in middle-aged and elderly individuals in skin with chronic sun exposure. SCC is a malignant skin tumor, which arises in the epidermis. They typically present in areas of hyperkeratosis (thickening of the outer skin layer) and approximately 65% arise from actinic keratosis. The most common location of squamous cell carcinomas is the face. Other areas at high risk include the back, shoulders, forearms and hands, and lower legs.
The appearance of squamous cell carcinoma is typically a small, painless, elevated and crusty lump. As the lesions grow, they can become an ulceration and may bleed. SCCs tend to develop more rapidly than BCCs, and unlike BCC, SCC can spread to the local lymphatic system. Risk factors for lymph node involvement include tumors > 3 cm, poorly differentiated pathology, recurrent tumors, and tumors with > 4 mm depth of invasion. They can also be rather aggressive locally, causing significant damage and disfiguration to local structures. Risk factors for recurrence after treatment of squamous cell carcinomas include perineural invasion, tumor thickness, and poorly differentiated histology.
Staging of Non-Melanoma Skin Cancers
When non-melanoma skin cancer is suspected, a biopsy is frequently performed to establish the diagnosis. This biopsy removes the lesion and the layers beneath it, allowing the depth of the lesion to be accurately determined. The depth of the lesion determines prognosis and treatment, so it is important for this to be accurate. This depth is described by Clark's level, which describes depth of invasion by the tissue it invades (levels I-V). Clark's Level I involves the epidermis only (outermost level). Clark's Level II involves the epidermis and the layer of skin immediately below, the papillary dermis. Clark's Level III goes one layer deeper into the reticular dermis. Clark's Level IV involves the deep dermis. Clark's Level V invades beyond the skin layers into the subcutaneous fat. Clark's level is an indication of the depth of penetration only, not the stage of disease.
Non-melanoma skin cancer is most commonly staged using the TNM staging system, which is determined by the American Joint Committee on Cancer 7th edition (2010) The "T stage" represents the extent of the primary tumor itself. The "N stage" represents the degree of involvement of the lymph nodes. The "M stage" represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows:
High Risk Features
The staging can be further condensed into a stage group, which takes the various combinations of TNM and places them into groups designated stages 0-IV.
Although this system of cancer staging is quite complicated, it is designed to help physicians describe the extent of the cancer, and therefore, helps to direct what type of treatment is given.
Treatment of Non-melanoma Skin Cancer
The treatment of SCC and BCC is dependent on location of the tumor, the age of the individual at diagnosis, the extent of disease, and whether the area has been treated before. Non-melanoma skin cancers are generally addressed with local treatments, including surgery, cryotherapy, and radiation. When lesions are discovered and thought to be suspicious, they are frequently biopsied to ensure they are not a more aggressive type of skin cancer. For lesions that are small and not locally progressive, the treatment options are numerous and include Moh’s surgery, excisional surgery, cryotherapy, curettage and electrodessication, photodynamic therapy, topical chemotherapy, and radiation therapy. Let’s review these treatment options.
Cryotherapy: This type of treatment involves freezing off the lesions with liquid nitrogen. Cryotherapy is best for very small, well-defined superficial BCC and well-demarcated SCC. It is frequently used in patients that are not ideal surgical candidates.
Excisional surgery: This traditional simple surgical resection involves numbing the area with local anesthesia and removing the entire area of concern with a border or margin of healthy tissue, generally 3-10 mm. The skin is then closed with sutures (stitches) and the tissue is sent to a laboratory for a pathologist to ensure all the cancer has been removed. The recurrence rate for tumors greater than 1.5 cm is about 10% at 5 years. If the tumor is greater than 3 cm, the recurrence rate can be more than 20% at 5 years.
Curettage and electrodessication: The type of therapy is the most common method for treating BCC. The treatment involves local anesthesia followed by removal of the tumor by curettage (scraping). The abnormality is scooped out with a curette until normal skin is appreciated. The entire area is then treated with an electrical current to stop any bleeding. The difficulty with curettage is found in evaluating the margins (edges) and depth of the tumor. Similar to cryotherapy, this technique is best for very small, well-defined superficial BCC and well-demarcated SCC. Tumors less than 0.5 cm have a 15% recurrence rate. With tumors > 3 cm, recurrence rates can approach 50% in some patient populations.
Moh’s surgery is a procedure often performed by a dermatologist or a trained specialist in the office under local anesthesia. With Moh’s surgery, very precise surgery is performed with attempts to remove the least amount of tissue while the margins, or edges, of the resection are examined under a microscope immediately to ensure all of the cancer is removed. While other types of resection can have recurrence rates as high as 50%, Moh’s cure rates have been documented higher than 90%. This type of surgery is also very useful in traditionally difficult areas, including the face. Indications for Moh’s surgery include large lesions where cosmesis can be difficult and maximum skin preservation is crucial.
Radiation therapy, which involves the use of non-invasive, painless, highly focused beams of ionizing energy, is often used when lesions are in locations that are not easily addressed with surgery, such as eyelids, lips, the nose, or ears. Radiation therapy involves daily treatments for several weeks. Radiation is used in the primary treatment of non-melanoma skin cancers, achieving local control nearing 90%. Radiation is more frequently used for skin cancers in the head and neck region as it offers improved cosmetic outcomes. The effectiveness of radiation as a primary treatment is related to tumor size, with smaller tumors generally responding better. As late skin effects from radiation are a concern, radiation is generally reserved for older patients. Radiation therapy can also be used in conjunction with surgery when tumors are considered high risk or have positive margins as well as with recurrent tumors.
Topical medications and chemotherapies: Topical medications are occasionally used to treat BCC. 5- Fluorouracil (5-FU) is a type of chemotherapy often used intravenously for other types of cancer; however, it is also approved for topical use for basal cell carcinomas. The 5-FU cream is applied to the area twice daily for several weeks. Imiquimod is also an approved topical medication for BCC. This cream, which is thought to work by stimulating the immune system, is applied to the tumor five times a week for 6 weeks. This type of therapy is reserved for pre-malignant and very superficial lesions.
For locally advanced lesions that involve invasion into adjacent areas, the treatments are typically more aggressive. Frequently, the surgery will involve reconstruction if a large amount of tissue will be removed. When reconstruction must occur, a skin graft or muscle is often used to aid healing and reach an acceptable cosmetic outcome. Radiation therapy will be used in addition to surgery to improve local control for lesions that are large and / or total resections are not possible. When tumors recur at the primary (original) site, treatment becomes more complex and is often referred to specialists. The majority of recurrences occur within the first few years following diagnosis. When possible, surgery to achieve negative margins is the best option. However, as lesions often occur on the face near important structures such as the nose, lips, ears, and eyes, radiation is often used when surgery would results in disfigurement.
When draining lymph nodes are suspected, particularly with SCC, the lymph nodes should be removed as one lump of tissue to be examined microscopically.
Follow up Testing
Patients with a history of non-melanoma skin cancer have been documented to have up to a 40% chance of developing a second skin cancer in the three years following their original diagnosis. Therefore, all patients require close follow-up. Patients with BCC should be evaluated with a complete skin exam every 6 months for life. Patients with localized SCC should be evaluated with a complete skin exam every 3 to 6 months for the first 2 years after diagnosis, then every 6 to 12 months for 3 years, and then annually.
Patients with regional SCC (involving the lymph nodes) should be followed more closely and be seen by a healthcare provider every 1 to 3 months for 1 year, then 2 to 4 months for the next year, then 4 to 6 months for years 3-5, then every 6 to 12 months for life.
This article is meant to give you a better understanding of non-melanoma skin cancer. Use this knowledge when meeting with your healthcare provider, making treatment decisions, and continuing your search for information.
References & Further Reading
Alam, M. &Ratner, D. Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2001; 344:975-983.
American Cancer Society. Skin Cancer: Basal and Squamous Cell. www.americancancersociety.com
DeVita, VT, Lawrence, TS, Rosenberg SA, Weinberg, RA, DePinho, RA. Cancer: Principles & Practice of Oncology. Wolters Kluwer/Lippincott Williams & Wilkins (2008).
Haffty, BG, Wilson, LD. Handbook of Radiation Oncology: Basic Principles and Clinical Protocols. Jones and Bartlett Publishers (2008).
Hansen, EK & Roach, M. Handbook of Evidence-Based Radiation Oncology. Springer (2010).
Martinez, JC & Clark CC. The Management of Melanoma and Nonmelanoma Skin Cancer: A Review for the Primary Care Physician. Mayo Clinic Proceedings December 2001 vol. 76 no. 12 1253-1265
Neville JA, Welch, E, & Leffell, DJ. Management of nonmelanoma skin cancer in 2007. Nature Clinical Practice Oncology (2007) 4, 462-469
Preston, D & Stern RS. Nonmelanoma Cancers of the Skin. N Engl J Med 1992; 327:1649-1662.